The senile plaque is a pathological hallmark of Alzheimer's disease (AD) and is composed of beta amyloid fibrils (fAbeta), activated microglia and astrocytes, and degenerating neurons. A key early step in plaque formation is the migration of microglia to sites of fAbeta deposition where they contribute significantly to neuronal degeneration. We hypothesize that fAbeta activates local microglia to produce chemokines (chemoattractant cytokines) that recruit additional microglia to the plaque. Recruited microglia bind to fA( and become activated to produce neurotoxins and other inflammatory mediators that cause neuronal damage. Activated microglia are then retained in the senile plaque and continue to produce neurotoxins. We propose to determine the molecular mechanism of recruitment, activation and retention of microglia in senile plaques in AD. We have preliminary data demonstrating that a subset of chemokines, namely, MCP-1, MIP-1alpha, MIP-1beta, MIP-2 and KC, are induced in microglia following fAbeta stimulation and that their respective receptors, CCR2, CCR5 and CXCR2 are expressed and functional on microglia. We have also generated new preliminary data demonstrating that CCR2 is required for early recruitment of microglia to sites of intracerebral fAbeta microinjection in vivo and that the scavenger receptor CD36 is an essential component of the cell surface receptor complex necessary for microglia to produce chemoattractants in response to fAbeta. These data have lead us to our central hypothesis that we will test in this proposal that CCR2, CCR5 and CXCR2 and their respective ligands, MCP-1, MIP-1alpha, MIP-1beta, MIP-2 and KC, are the key chemokine/chemokine receptors that mediate the chemoattraction of microglial cells to sites of fAbeta deposition. To test this hypothesis we will use: (a) an in vitro model for microglial cell chemotaxis; (b) an in vivo short-term model of fAbeta-induced microglial cell recruitment to sites of intracerebral deposition, and (c) transgenic APP mice Tg2576 (APP-Tg) that develop AD-like pathology. Specifically we propose to: 1) Define the role of CCR2, CCR5 and CXCR2 in mediating fAbeta-induced microglial cell chemotaxis in vitro; 2) Determine the role of CCR2, CCR5 and CXCR2 in mediating the recruitment of microglia to sites of intracerebral fA( deposition in vivo; and 3) Determine the role of CD36 in the regulation of chemokine production in vivo in APP-Tg mice and determine the role of CD36 and CCR2 (and CCR5 and CXCR2 if indicated) in the recruitment of microglia and formation of fA( deposits in APP-Tg mice. Chemokines and their receptors are attractive therapeutic targets in many inflammatory processes. Understanding the role of chemokines in recruitment, activation and retention of microglia in AD may lead to exciting novel therapeutic targets to delay the progression of AD by delaying or inhibiting the accumulation and activation of microglia at sites of fAbeta deposition.